Nabiximols is Efficient as Add-On Treatment for Patients with Multiple Sclerosis Spasticity Refractory to Standard Treatment: A Systematic Review and Meta-Analysis of Randomised Clinical Trials

Background Spasticity affects 54% of multiple sclerosis (MS) patients at disease onset, but this rate gradually increases with disease progression. Spasticity does not fully respond to standard treatment in one-third of the patients. Objective Our systematic review and meta-analysis assessed whether add-on nabiximols, can improve MS-associated refractory spasticity. Methods The systematic literature search was performed in Web of Science, MEDLINE, Scopus, CENTRAL, and Embase, on 15/10/2021, without restrictions. We included in the review blinded, randomized, placebo-controlled trials evaluating the efficacy of nabiximols in adult MS patients with refractory spasticity, by comparison with placebo. The primary outcome was responder rate by spasticity numerical rating scale (NRS). Secondary outcomes were spasticity-related parameters. We used random effect models to calculate odds ratios (OR) or mean differences and the corresponding 95% CI. Bias-factors were assessed with Cochrane risk of bias tool (RoB2). (PROSPERO ID: CRD42021282177). Results We identified 9 eligible articles, of which 7 (1128 patients) were included in the meta-analysis. The spasticity numerical rating scale (NRS) was significantly higher in the nabiximols group than in the placebo group (OR 2.41 (95% CI 1.39; 4.18)). Secondary outcomes were in accordance with our primary results. At least some concerns were detected in the risk of bias analysis. Conclusion Our results indicate that nabiximols is efficient in MS associated spasticity, refractory to standard treatment and it may be considered as add-on symptomatic therapy. Nevertheless, further studies are needed to establish the optimal treatment protocol – dose, duration, moment of initiation, disease type.


Eligibility criteria 5
Specify the inclusion and exclusion criteria for the review and how studies were grouped for the syntheses.2 Information sources 6 Specify all databases, registers, websites, organisations, reference lists and other sources searched or consulted to identify studies.Specify the date when each source was last searched or consulted.
2 Search strategy 7 Present the full search strategies for all databases, registers and websites, including any filters and limits used.

2
Selection process 8 Specify the methods used to decide whether a study met the inclusion criteria of the review, including how many reviewers screened each record and each report retrieved, whether they worked independently, and if applicable, details of automation tools used in the process.
2 Data collection process 9 Specify the methods used to collect data from reports, including how many reviewers collected data from each report, whether they worked independently, any processes for obtaining or confirming data from study investigators, and if applicable, details of automation tools used in the process.

Data items 10a
List and define all outcomes for which data were sought.Specify whether all results that were compatible with each outcome domain in each study were sought (e.g. for all measures, time points, analyses), and if not, the methods used to decide which results to collect.

2-3 10b
List and define all other variables for which data were sought (e.g.participant and intervention characteristics, funding sources).Describe any assumptions made about any missing or unclear information.

2-3; 10
Study risk of bias assessment 11 Specify the methods used to assess risk of bias in the included studies, including details of the tool(s) used, how many reviewers assessed each study and whether they worked independently, and if applicable, details of automation tools used in the process.

3
Effect measures 12 Specify for each outcome the effect measure(s) (e.g.risk ratio, mean difference) used in the synthesis or presentation of results.

2-3
Synthesis methods 13a Describe the processes used to decide which studies were eligible for each synthesis (e.g.tabulating the study intervention characteristics and comparing against the planned groups for each synthesis (item #5)).

13b
Describe any methods required to prepare the data for presentation or synthesis, such as handling of missing summary statistics, or data conversions.

2-3 13c
Describe any methods used to tabulate or visually display results of individual studies and syntheses.

2-3 13d
Describe any methods used to synthesize results and provide a rationale for the choice(s).If metaanalysis was performed, describe the model(s), method(s) to identify the presence and extent of statistical heterogeneity, and software package(s) used.

2-3 13e
Describe any methods used to explore possible causes of heterogeneity among study results (e.g.subgroup analysis, meta-regression).

2-3 13f
Describe any sensitivity analyses conducted to assess robustness of the synthesized results.

2-3
Reporting bias assessment 14 Describe any methods used to assess risk of bias due to missing results in a synthesis (arising from reporting biases).

3
Certainty assessment 15 Describe any methods used to assess certainty (or confidence) in the body of evidence for an outcome.

Study selection 16a
Describe the results of the search and selection process, from the number of records identified in the search to the number of studies included in the review, ideally using a flow diagram.

3-4 16b
Cite studies that might appear to meet the inclusion criteria, but which were excluded, and explain why they were excluded.

Study characteristics 17
Cite each included study and present its characteristics.4 Risk of bias in studies 18 Present assessments of risk of bias for each included study.8; Suppl material

Results of individual studies 19
For all outcomes, present, for each study: (a) summary statistics for each group (where appropriate) and (b) an effect estimate and its precision (e.g.confidence/credible interval), ideally using structured tables or plots.

4-8
Results of syntheses 20a For each synthesis, briefly summarise the characteristics and risk of bias among contributing studies.

4-8 20b
Present results of all statistical syntheses conducted.If meta-analysis was done, present for each the summary estimate and its precision (e.g.confidence/credible interval) and measures of statistical heterogeneity.If comparing groups, describe the direction of the effect.

Fig
Fig. (S1).Nabiximols alleviates multiple sclerosis associated spasticity more effectively than placebo in terms of symptom severity measured by numerical rating scale in long-term studies (treatment duration ≥ 6 weeks).For this analysis Novotna et al. (2011) was excluded, because of the differing baseline.Abbreviations: CI: confidence interval; MD: mean difference; NRS: numerical rating scale Abbreviations: ADL: activities of daily living; CI: confidence interval; mAS: modified Ashworth scale; NRS: Numerical rating scale; OR: odds ratio; SGIC: subject's global impression of change

Table S1b . For the evaluation of spasticty NRS recalculations had to be performed for a study
Abbreviations: NRS: numerical rating scale; VAS: visual analog scale.

Table S1d . For the evaluation of mAS recalculations had to be performed for a study.
Abbreviation: mAS: modified Ashworth scale

Abbreviations: ADL: activities of daily living Table S1g. Evaluation of SGIC
Abbreviations: SGIC: subject's global impression of change